The Role of Aspirin in HIV & Aging: Pro-Standpoint

Transcription

1 The Role of Aspirin in HIV & Aging: Pro-Standpoint Virginia Triant Massachusetts General Hospital 6 th International Conference on HIV and Aging October 6, 2015

2 None Disclosures

3 Questions for Debate Should aspirin (ASA) be considered in HIV-infected persons with 10-year risk of atherosclerotic cardiovascular disease (ASCVD) >7.5%? Is a randomized controlled trial of ASA to prevent vascular events in HIV indicated?

4 Aspirin Mechanism of Action Nonsteroidal anti-inflammatory drug (NSAID) Anti-inflammatory, antithrombotic, antipyretic, and analgesic Antithrombotic effect: inhibits platelet production of thromboxane A 2 (TXA 2 ) decreases platelet aggregation Antipyretic/analgesic: inhibits COX-1 and COX-2 blocks prostaglandin production COX-1 involved in platelet aggregation COX-2 expressed in inflammation Anti-inflammatory: mechanism in part prostaglandin-related Davi NEJM 2007;

5 Aspirin Mechanism of Action Prostaglandin and thromboxane synthesis Davi NEJM 2007;

6 Aspirin Mechanism of Action Anti-inflammatory effects via prostaglandinindependent actions Inhibition of expression of inducible nitric oxide synthase and generation of nitric oxide Inhibition of activation of NF-kappa B, transcription factor involved in inducible expression of factors including IL-6 and TNF Inhibition of neutrophil activation and adhesiveness Higher doses required for anti-inflammatory than antithrombotic effect as COX-2 is inhibited less efficiently than COX-1 Davi NEJM 2007;

7 Aspirin for Primary Prevention of CVD USPSTF most recent published recommendation statement Ann Intern Med 2009.

8 Aspirin for Primary Prevention of CVD USPSTF recently released new draft recommendation statement on low-dose aspirin use for primary prevention of CVD and colorectal cancer Accessed October 2, 2015.

9 Aspirin for Primary Prevention of CVD Accessed October 2, 2015.

10 Aspirin Underused in HIV Fewer than 1 in 5 patients (17%) who qualified to receive ASA for primary prevention received it in large HIV clinic 2009 US Preventive Services Task Force Guidelines Odds of ASA use increased with each additional CVD risk factor In another study, 31% of patients met criteria for ASA yet 1.6% received it Burkholder CID 2012; Tornero JAIDS 2010.

11 Aspirin Use in HIV Lower than Controls Prevalence of ASA Use in Low CHD Risk Prevalence of ASA Use in High CHD Risk* Prevalence (%) Prevalence (%) Overall Women Men 0 Overall Women Men HIV-infected HIV-uninfected HIV-infected HIV-uninfected Suchindran OFID 2014.

12 Pro-Standpoint Aspirin should be considered in HIVinfected persons with 10-year risk of atherosclerotic cardiovascular disease (ASCVD) >7.5%? Aspirin should be used more aggressively in HIV patients than in comparable general population patients

13 Pro-Standpoint HIV patients have traditional and novel CVD risk factors that can be modulated by ASA Increased rates of traditional CVD risk factors Novel CVD risk factors related to inflammation and immune activation ASA has been shown to be an effective antithrombotic and antiinflammatory in HIV Increased platelet dysfunction and immune activation in HIV ASA decreases platelet dysfunction and immune activation in HIV CVD risk prediction algorithms may underestimate risk in HIV Traditional CVD risk factors may not be appropriately weighted Novel CVD risk factors are not captured Different thresholds may be needed in HIV

14 Pro-Standpoint HIV patients have traditional and novel CVD risk factors that can be modulated by ASA Increased rates of traditional CVD risk factors Novel CVD risk factors related to inflammation and immune activation ASA has been shown to be an effective antithrombotic and antiinflammatory in HIV Increased platelet dysfunction and immune activation in HIV ASA decreases platelet dysfunction and immune activation in HIV CVD risk prediction algorithms may underestimate risk in HIV Traditional CVD risk factors may not be appropriately weighted Novel CVD risk factors are not captured Different thresholds may be needed in HIV

15 Elevated Rates of Traditional CVD Risk Factors in HIV Rate Per 100 Persons HIV+ HIV- Hypertension Diabetes Dyslipidemia Diagnosis (By ICD Code) Smoking in HIV Heightened rates 56% (D:A:D) 54% (SFGH) 47% (US cohort) 69% (French cohort) 85% lifetime history Significantly higher than non- HIV patients Triant JCEM 2007; Burkhalter Nicotine Tob Res 2005; Friis-Moller AIDS 2003; Mamary AIDS Pt Care STDs 2002; Gritz Nicotine Tob Res 2004; Vittecoq AIDS 2003; Savès CID 2003; Lifson AJPH 2010.

16 Novel CVD Risk Factors in HIV: Inflammation and Immune Activation SMART study showed increased CVD event rates in drug conservation (episodic treatment) vs. viral suppression (continuous treatment) group HR=1.57, P=0.05 Primary endpoint recurrent OI/death Inflammatory markers IL-6 and d-dimer increased 1 month after treatment interruption in SMART Baseline hscrp, IL-6, and d- dimer strongly correlated to overall mortality El-Sadr NEJM 2006; Phillips AIDS 2008; Kuller PLoS 2008.

17 Novel CVD Risk Factors in HIV: Monocyte Activation Immune activation markers, including markers of monocyte activation (scd163), are significantly linked to: Presence of non-calcified vulnerable plaque High-risk morphology plaque Arterial inflammation (aortic TBR) Control HIV 0 Low Attenuation Plaque Positively Remodeled Plaque % subjects with vulnerable plaque Burdo JID 2011; Zanni AIDS 2013; Subramanian JAMA 2012.

18 Pathophysiology of HIV-Associated CVD ART ART VIRAL REPLICATION DYSLIPIDEMIA INFLAMMATION IMMUNE ACTIVATION MICROBIAL TRANSLOCATION CVD DIABETES HYPERTENSION SMOKING Increase risk Decrease risk GENETICS

19 Pro-Standpoint HIV patients have traditional and novel CVD risk factors that can be modulated by ASA Increased rates of traditional CVD risk factors Novel CVD risk factors related to inflammation and immune activation ASA has been shown to be an effective antithrombotic and antiinflammatory in HIV Increased platelet dysfunction and immune activation in HIV ASA decreases platelet dysfunction and immune activation in HIV CVD risk prediction algorithms may underestimate risk in HIV Traditional CVD risk factors may not be appropriately weighted Novel CVD risk factors are not captured Different thresholds may be needed in HIV

20 Platelet Activation Increased and Linked to Immune Activation in HIV Platelet activation increased in HIV patients versus controls As measured by P-selectin and CD63 Platelet aggregation in response to some platelet agonists increased in several studies Platelets in HIV patients have lower threshold to activation Dose-dependent hyper-reactivity HIV-activated platelets in turn activated monocytes Direct role for activated platelets in immune activation Holme FASEB J 1998; Satchell AIDS 2010; O Brien JAIDS 2013.

21 Aspirin Decreases Platelet Activation and Immune Activation in HIV 1 week of low-dose ASA: Decreased percent platelet aggregation similarly in HIV and control patients in response to all except one agonist Attenuated T cell and monocyte activation ASA may decrease immune activation in HIV Directly through inflammatory pathways Indirectly through inhibition of platelet activation O Brien JAIDS 2013.

22 ACTG Aspirin Study Modulation of Immune Activation by Aspirin Interventional study assessing changes in immune activation with 12 weeks of ASA therapy Primary outcome change in scd14 from baseline to week 12 Secondary outcomes multiple immune, inflammatory and thrombotic markers Accessed October 4, 2015.

23 Abacavir and Platelet Dysfunction Platelet reactivity increased in patients on abacavir-containing ART versus non-abacavircontaining ART Abacavir associated with platelet hyperreactiviy Competitively inhibits guanylyl cyclase Abacavir associated with reversible platelet dysfunction Decreased ADP responsiveness and integrin β3 and platelet receptor levels Suggests presence of immature platelets Satchell JID 2011; Baum AIDS 2011; Trevillyan et al. Abstract 736, CROI 2015.

24 Pro-Standpoint HIV patients have traditional and novel CVD risk factors that can be modulated by ASA Increased rates of traditional CVD risk factors Novel CVD risk factors related to inflammation and immune activation ASA has been shown to be an effective antithrombotic and antiinflammatory in HIV Increased platelet dysfunction and immune activation in HIV ASA decreases platelet dysfunction and immune activation in HIV CVD risk prediction algorithms may underestimate risk in HIV Traditional CVD risk factors may not be appropriately weighted Novel CVD risk factors are not captured Different thresholds may be needed in HIV

25 New CVD Risk Assessment Guidelines New ACC/AHA guidelines on CVD risk estimation released in 2013 New CVD risk prediction equation employed (Pooled cohorts equation) Reports of overestimation of risk in the general population Goff Circulation 2014.

26 ACC/AHA Calculator Overestimates Risk Primary prevention cohorts ACC/AHA risk prediction algorithm systematically overestimated observed risk in general population Degree of risk overestimation % Overestimation observed by guideline developers in 2 additional external validation cohorts Recent study from Women s Health Study also observed overestimation of risk Ridker Lancet 2013; Cook JAMA IM 2014, Kavousi JAMA 2014.

27 CVD Risk Prediction Algorithms Underestimate Risk in HIV 25 FRS 25 ACC/AHA Year Event Rate (%) Year Event Rate (%) <2.5% % % 5 Year Predicted Risk % 0 <2.5% % % 5 Year Predicted Risk % Predicted Observed Predicted Observed Partners HIV longitudinal cohort, 2239 patients Algorithms underestimate CVD risk in HIV, comparing observed to predicted rates To identify HIV patients at a target predicted CVD risk category, a lower threshold may need to be used (e.g. use 7.5% in HIV vs 10% in the general population) Regan CROI 2015, abstract 751.

28 CVD Outcome Rates by Predicted Risk Category in HIV Cohort 10-Yr ASCVD Risk LDL N Events Rate/1000P Y 95% CI LL 95% CI UL <7.5 < < < <10 < < < <15 < < < <17.5 < < < <20 < < < Triant, preliminary data.

29 Questions for Debate Should aspirin (ASA) be considered in HIV-infected persons with 10-year risk of atherosclerotic cardiovascular disease (ASCVD) >7.5%? Is a randomized controlled trial of ASA to prevent vascular events in HIV indicated?

30 Aspirin Use in HIV: Conclusions Adhere to general population guidelines at minimum Consider lower threshold for ASA use than that used in general population if no contraindication USPSTF draft recommendations: consider 7.5% as a threshold rather than 10 (ACC/AHA risk score) Tailor based on gender, age, and predicted 10-year CVD risk Consider ASA use in HIV patients on abacavir-containing ART Use ASA in combination with other CVD risk reduction strategies A trial of ASA for CVD risk reduction in HIV would enhance current knowledge Consider trial in combination with other immunomodulatory interventions Consider marker of preclinical atherosclerosis as outcome HIV patients merit aggressive CVD risk reduction as a population